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Key Event Title
Cellular Proliferation and Clonal Expansion of Mutant Cells (Pre-neoplastic Foci), Alteration of cellular growth homeostasis
Key Event Components
Key Event Overview
AOPs Including This Key Event
Key Event Description
The occurrence of altered hepatic foci (AHF) as precursors to liver tumors in AFB1-treated rats has been recognized for decades. Originally, these foci were observed as histologically different from the surrounding parenchyma. (Harada et al., 1989, 1990; Gil et al., 1988; Bannasch et al., 1985). In addition, enzyme alterations were used to identify AHF foci, most notably, the occurrence of a placental form of glutathione-S-transferase (GSTP+). (Godlewski et al., 1985; Dragan et al., 1994a, 1995; Kirby et al., 1990) The growth and occurrence of foci are expressed as the number of AHF in a volume of liver, possibly the entire liver, and the volume fraction of the liver occupied by AHF. (Dragan et al., 1997) Both of these reflect focal growth because single cell foci are not detectable with the immunohistochemical staining technique. The assumption is that single transformed cells in which apoptosis is blocked by tumor-critical mutations will grow into AHF. (Grassl-Kraupp et al., 1997). A number of agents regarded as tumor promoters appear to enhance the growth of foci, acting further to inhibit apoptosis and also creating an overall proliferative stimulus. (Angsubhakorn et al., 2002; Wyde et al., 2002).
AFB1 appears to be a “complete” carcinogen in that the toxin acts as an initiator through the formation of pro-mutagenic DNA adducts (the MIE) and as a promoter through increasing oxidative stress and inflammation. (Ohnishi et al., 2013; Caballero et al., 2004).
Evidence Supporting Essentiality
Chemoprevention studies, reviewed in another section of this AOP, suggest a strong relationship between altered hepatic foci (AHF) and HCC tumor formation (Olden and Vulimiri, 2014; Liby et al., 2008; Yates et al., 2007; Yates and Kensler, 2007; Kensler et al., 2004). For example, Johnson et al. (2014) observed background levels of AHF along with a complete absence of tumors in rats treated with a triterpenoid chemoprotectant CDDO-Im, despite maintaining a significant burden of AFB1-induced adducts. (Johnson et al., 2014) Cell proliferation appears to be six- to seven-fold greater in AHF than in surrounding liver parenchyma. (Dragan et al., 1994) However, the measurements were made from liver biopsies, and whether the increased expression was associated with foci is not known.
How It Is Measured or Detected
Quantitative stereology has been used to quantify the growth of AHF (Pitot et al., 1996; Dragan et al., 1995; Xu et al., 1990). Growth of foci appears to follow the Moolgavkar-Venzon-Knudson model of initiation and promotion. (Dewanji et al., 1991; Dragan et al., 1995) Most recently, Johnson et al. (2014) have shown that a chemoprotective agent reduces the occurrence of AHF to background levels and completely protects against tumors, although pro-mutagenic adducts are still present at easily quantifiable levels.
Domain of Applicability
The occurrence of AHF appears to be universal and has been observed in mammals, including humans, as well as in birds and in fish. (Ribback et al., 2013; Thoolen et al., 2012; Kirby et al., 1990).
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